At the Crossroad Between Skeletal and Cardiac Muscle Cells

Christopher R. deFilippi, MD; Abdulla A. Damluji, MD, PhD

Disclosures

Circulation. 2022;145(24):1780-1783. 

In 1510, Leonardo Da Vinci was the first to describe the heart muscle as arranged in longitudinal and transverse fibers, the contraction of which resulted in shortening and widening of the ventricular cavities.[1] Since then, there has been a divergence in the study of cardiac and skeletal muscle cells because of the complexity of the structure and function of cardiac myocytes. In this issue of Circulation, du Fay de Lavallaz et al,[2] reporting the findings of the 4-hospital–based Heart & Muscle BASEL XII Study, have in part circled back by producing conclusive evidence of the shared pathophysiology between these 2 muscle types with the expression of the cardiac isoform of troponin (cTn) T in chronic skeletal myopathies and myositis.[2]

The investigative team examined circulating levels of cTnT and cTnI using 1 cTnT and 3 cTnI widely used commercial high-sensitivity (hs) assays among 211 patients with several skeletal muscle diseases (SMDs), including myopathy, myositis, neuropathy, myasthenic syndrome, autoimmune disease, and nonspecific muscle symptoms, enrolled from inpatient (11%) or elective ambulatory clinics (89%) in general medical or specialized neuromuscular and rheumatology services. The investigators found that approximately half of the participants with SMD had some form of cardiovascular disease (CVD), and most commonly this was attributable to coronary heart disease. There was a dose–response relationship between the severity of known CVD and cardiac myocyte injury and higher levels of both hs-cTnT and hs-cTnI. The hs-cTnT values were above the upper limit of normal (ULN) in 55% of the study population with SMD, with a median level of 16 ng/L versus 5 ng/L for control subjects (patients in the emergency department with adjudicated noncardiac chest pain [n=3508]), whereas hs-cTnI levels, measured by the 3 other commercial assays, were at most elevated in 23% among those with SMD, and median levels were nearly identical to those of control subjects for all 3 assays. This observation was more remarkable when the subgroup without known CVD was evaluated; SMD resulted in 37% of the hs-cTnT levels above the ULN versus 2% to 8% with the hs-cTnI assays. Elevations in hs-cTnT among patients without underlying CVD were found mostly among patients with noninflammatory myopathy or inflammatory myositis, which correlated with creatine kinase, a biomarker of skeletal muscle damage. In contrast, there was no correlation with cTnI levels measured by any of the 3 hs-cTnI assays and creatinine kinase. Aiming to establish causal associations, the investigators also measured cTn-specific mRNA from muscle biopsies in 33 patients with SMD and then 16 control subjects having elective hip surgery. They found an 8-fold upregulation of TNNT2 mRNA expression (coding cTnT) compared with control subjects, which correlated with circulating hs-cTnT concentrations, but there was no upregulation of mRNA coding for cTnI.

The work by du Fay de Lavallaz et al supports the earlier associations between elevated circulating hs-cTnT levels and various myopathies ascertained by biopsies.[3,4] The elevation in cTnT was observed previously in skeletal myopathies regardless of whether the underlying muscle injury was endocrine, metabolic, autoimmune, genetic, neurally mediated, or caused by drug toxicity.[3] Although the results are robust and corroborated with previous evidence, as with most well-conducted studies, a path is opened to ask more questions about the clinical implications of the dichotomization of diseased skeletal muscle to express cTnT and not cTnI beyond a highly select group of patients with symptomatic skeletal muscle myopathies or myositis. First, as we recently described, there are many asymptomatic patients with malnutrition, sarcopenia, frailty, or even cachexia who phenotypically exhibit interrelated pathophysiological processes leading to different magnitudes of wasting and may be susceptible to muscle pathophysiologic changes similar to those in patients with active chronic muscular complaints.[5,6] Recently an "omics" approach using machine learning across 4 older adult cohorts showed that cTnT was one of the circulating proteins most strongly associated with prefrailty and frailty with and without disability.[7] Second, the impact of the findings by du Fay de Lavallaz on patients with suspected or known SMD during acute presentations needs to be carefully considered. In many cases, the levels of both cTnT and cTnI will often be at least several-fold higher than the ULN, but given that 55% of the study population had levels above the hs-cTnT ULN, levels closer to the 99th percentile established ULN will need appropriate clinical caution, and the short-term longitudinal change in circulating levels of patients with SMD may need further study. Third, although biological plausibility is ascertained in this study, the strength of the association between elevated hs-cTnT and long-term incident CVD outcomes among patients with active muscle complaints remains unknown and warrants additional investigation.

Cardiovascular clinicians are regularly tasked to care for complex patients living with multiple chronic conditions, and these conditions often confound clinical decision making. SMD often requires a high level of clinical suspicion, and the interpretation of diagnostic testing among these patients poses challenges. With assimilation of the findings from the present study, perhaps most interesting is the (re)interpretation of hs-cTnI and hs-cTnT for prognosis in ambulatory adults. For more than a decade, it has been recognized that cTnT and cTnI measured with high-sensitivity assays identify ambulatory patients who are free of prevalent CVD, have known coronary heart disease, or have chronic kidney disease who are at increased risk of CVD hospitalization and death.[8,9] High-sensitivity assays for cTnI and cTnT can be used interchangeably for the diagnosis of acute myocardial infarction, with both assays showing equivalent accuracy and a high correlation (Pearson r=0.89), but the same may not be true in ambulatory cohorts.[10] In the ARIC study (Atherosclerosis Risk in Communities) evaluating participants without prevalent CVD and the PEACE trial (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy) evaluating participants with stable coronary heart disease without heart failure, the same hs-cTnT and hs-cTnI assay results were only moderately correlated (r=0.47 and r=0.44, respectively).[8,11] Unlike acute myocardial infarction evaluations, this discordance between hs-cTnT and hs-cTnI results among ambulatory participants has translated into differences for predicting some, but not all, CVD events. For example, in the large community cohort Generation Scotland Scottish Family Health Study, progressively higher baseline hs-cTnI, but not hs-cTnT, levels predicted incident acute myocardial infarction.[12] A similar finding for incident acute myocardial infarction was seen in PEACE.[8] In contrast, in the same studies, both hs-cTnT and hs-cTnI have similar accuracy for the prediction of incident heart failure.[8,12]

In older adults, does skeletal muscle production of cTnT detectable by a high-sensitivity assay account for the discordance between circulating cTnT and cTnI levels? It is provocative that incident heart failure, which can be driven by systemic comorbidities (clinical or subclinical), particularly for heart failure with preserved ejection fraction, may be predicted equally well by a circulating biomarker potentially reflecting cardiac and SMD (cTnT) as a biomarker exclusive to cardiac injury (cTnI). However, a circulating biomarker exclusive to cardiac injury (cTnI) may be a more specific harbinger of coronary heart disease events. This does not mean that cTnT may not have an important role in the prediction of incident CVD (Figure). If future work bears out skeletal muscle production of cTnT in adults with prefrailty, frailty, or sarcopenia, the biomarker might ultimately find its way as a measure of the efficacy of physical activity on both skeletal and cardiac myocytes; pilot work in sedentary older adults has shown that a physical activity program can reduce the longitudinal trajectory of hs-cTnT levels.[13] As with most definitive well-conducted studies, the work du Fay de Lavallaz et al provides a big step forward with respect to the interpretation of hs-cTn in those presenting with known SMD but now challenges and potentially enhances our interpretation of hs-cTn results in a much broader at-risk ambulatory population.

Figure.

Potential sources of circulating cardiac troponin I and T and differences in long-term prognosis in ambulatory patients. Adults with prefrailty, frailty, or other comorbidities may have skeletal muscle loss or disorders that could result in cardiac troponin T (cTnT) production (left). Circulating cTnT, but not cardiac troponin I (cTnI), is measurable by high-sensitivity (hs) assays in patients without known cardiovascular disease but with skeletal myopathy or myositis (from du Fay de Lavallaz et al2) (middle). Prior longitudinal ambulatory studies show that both cTnI and cTnT levels are long-term prognosticators for incident heart failure, but hs-cTnI is more prognostic of incident myocardial infarction (right). ULN indicates upper limit of normal (defined as the 99th percentile value in a healthy adult population).

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